The availability of magnetic resonance imaging (MRI) devices has led to the use of MRI in medical examinations for the detection and diagnosis of disease states and other internal abnormalities. The continued use and development of MRI has stimulated interest in the development of pharmaceutical agents capable of altering MRI images in diagnostically useful ways. Pharmaceutical agents (MRI pharmaceuticals) which are currently favored by researchers in the field are suitably complexed paramagnetic metal cations. The use of pharmaceuticals in MRI imaging offers major opportunities for improving the value of the diagnostic information which can be obtained.
Radiopharmaceuticals, which are used in radioisotopic imaging in a manner analogous to MRI pharmaceuticals, are a well developed field. The knowledge existing in this field thus provides a starting point for the development of MRI pharmaceuticals. MRI pharmaceuticals must meet certain characteristics, however, which are either not required or are considerably less critical in the case of radiopharmaceuticals. MRI pharmaceuticals must be used in greater quantities than radiopharmaceuticals. As a result, they must not only produce detectable changes in proton relaxation rates but they must also be (a) substantially less toxic, thereby permitting the use of greater amounts, (b) more water soluble to permit the administration of a higher dosage in physiologically acceptable volumes of solution, and (c) more stable in vivo than their radiopharmaceutical counterparts. In vivo stability is important in preventing the release of free paramagnetic metals and free ligand in the body of the patient, and is likewise more critical due to the higher quantities used. For the same reasons, MRI pharmaceuticals which exhibit whole body clearance within relatively short time periods are particularly desirable.
Since radiopharmaceuticals are administered in very small dosages, there has been little need to minimize the toxicity of these agents while maximizing water solubility, in vivo stability and whole body clearance. It is not surprising therefore that few of the ligands developed for use as components in radiopharmaceutical preparations are suitable for use in preparation of MRI pharmaceuticals. A notable exception is the well known ligand diethylene triamine pentaacetic acid (DTPA), which has proved useful in forming complexes with both radiocations, pharmacologically suitable salts of which provided useful radiopharmaceuticals, and paramagnetic cations such as gadolinium, whose pharmacologically suitable salts have proved useful as MRI pharmaceuticals.
Certain groups of radiopharmaceuticals tend to localize in bone tissue, and are thus of use in providing diagnostic information concerning bone disorders. The properties of these agents which lead to their localization in bone also allow for them to localize in soft tissues bearing recognitions features in common with bone. Thus, many radiopharmaceuticals which localize in bone are known, or believed, to localize in soft tissues which are found to have gross, microscopic or chemical evidence for deposition of calcium salts (e.g., metastatic calcification), such as might occur in association with tissue injury. Thus, radiopharmaceuticals have shown localization in rhabdomyolysis of various origins, in collagen disorders and in other injured tissues. Localization of such agents in areas of myocardial infarction is an example of one application which has proven diagnostically useful. Radiopharmaceuticals which localize in bone have also been shown to localize in normal and malignant breast tissue, in pleural effusions, in infarctions of the spleen and bowel, inflammatory bowel disease, radiation injury, metastatic calcification, and in a variety of malignant tumors, etc. Regardless of the mechanism of such localization we herein refer to the soft tissues which concentrate agents which localize in bone as "bearing recognition features in common with bone." Exclusive of their localization in bone and tissues bearing recognition features in common with bone, these agents generally are distributed in the extracellular fluid spaces of the body and therefore can be used to provide information concerning the content and kinetics of the extracellular fluid of normal and abnormal tissues. One example of the clinical utility of this behavior is the detection of disruption of the blood brain barrier wherein extracellularly distributed agents abnormally localize in the region of such disruption. Most of the presently known agents which localize in bone are excreted from the body by the kidneys and therefore can be used to evaluate the renal excretory system. It is possible that such agents could be made more lipophilic such that they would be excreted by the liver, and therefore could be used to evaluate the hepatobiliary excretory system.
Agents which localize in bone and which provide MRI contrast enhancement could be used to perform similar diagnostic procedures employing radiopharmaceuticals which localize in bone. Given the substantially greater spatial and temporal resolution of MRI techniques, as compared to nuclear medical techniques, it is anticipated that useful diagnostic information could be obtained in abnormalities which were not detected using nuclear medical techniques, as for example in detection of small areas of tissue damage and/or in small regions of deposition of calcium salts. Moreover, fixation of MRI contrast enhancement agents in such tissue would be expected to increase the relaxivity of the agent by decreasing the molecular rotation rate thereby increasing signal intensity. However, known radiopharmaceutical agents which localize in bone are retained in the region of their deposition for very prolonged periods of time making them unsuitable for use as MRI contrast agents. Moreover, these "bone seeking" pharmaceuticals which contain phosphonate groups are also known to be relatively strong chelators of calcium ions and their administration at the dose and dose rate levels associated with the use of MRI contrast agents can be associated with induction of acute hypocalcemia and attendant cardiac arrest. At present, MRI contrast enhancement agents are not available which, while showing diagnostically useful localization in bone, also show near quantitative whole body clearance within acceptable time periods and which have low toxicity comparable to existing MRI contrast enhancement agents.
Most known MRI pharmaceuticals when administered in vivo do not by themselves localize in specific tissues, but instead generally distribute in extracellular fluid space in a nonspecific manner. One means of achieving localization of these inherently nonspecific pharmaceuticals in selected tissues is by conjugation with biomolecules which localize in the region of interest. Another means is by incorporating the complexes into bodies which localize in the region of interest. Hormones, albumins, liposomes, and antibodies have been mentioned in such attachments or incorporation. See Cries, H., et al., U.S. Pat. No. 4,647,447, Mar. 3, 1987.